POS0404 SOLUBLE LOW AFFINITY NERVE GROWTH FACTOR RECEPTOR (LNGFR) MAY REGULATE PAIN IN KNEE OSTEOARTHRITIS
Authors: A. Altaie, M. Campbell, R. Doyle, H. Owston, E. Jones, R. Feibel, S. Westbrook, D. Mcgonagle
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is a disease of the entire joint. OA causes significant pain that has been linked to increased neurotrophin concentrations, including mature nerve growth factor β-NGF<sup>[2]</sup>. β-NGF antagonism was efficacious in reducing OA pain in clinical trials but was associated with rapidly progressive OA<sup>[1]</sup>, hampering mainstream delivery of this treatment. β-NGF binds to tropomyosin receptor kinase A (TrkA) and low-affinity NGF receptor (LNGFR), a tumour necrosis factor receptor (TNFR) superfamily member. Given that TNFR superfamily member shedding regulates inflammation and immunity, soluble LNGFR (sLNGFR) shedding might be important in pain regulation<sup>[3]</sup> and association between these molecules and OA-related knee pain may point to an alternative, less harmful approach to β-NGF antagonism and pain reduction. <h3>Objectives</h3> Therefore, we investigated the association between (synovial fluid) SF levels of soluble LNGFR, TrkA, proNGF and NGF and other relevant neurotrophins with OA-related knee pain. Key cytokines involved in TNFR family receptor shedding were also investigated. <h3>Methods</h3> SF was procured from 42 subjects with severe OA at the time of arthroplasty. VAS pain scores were recorded pre-operatively. In-house developed ELISAs, commercial ELISAs and LEGENDplex™ were used to measure sLNGFR, TrkA, proNGF, β–NGF, other neurotrophins and cytokines including TNF-α. Statistical analysis was implemented using Graphpad Prism software, version 9.0. Data normality was analysed using Kolmogorov-Smirnov and Shapiro-Wilk testing. The Spearman rank correlation test and multivariate linear regression analyses were performed to assess the correlations. Statistical significance was defined as p&lt;0.05. <h3>Results</h3> VAS pain score positively correlated with β–NGF (r=0.34, p&lt;0.05) and TrkA (r=0.33, p&lt;0.05, r=0.32, p&gt;0.05). There was a positive association trend with NT-3 and BDNF with a negative trend for ProNGF. sLNGFR. The β–NGF/TrkA ratio showed a strong positive correlation with VAS (r=0.80, p&lt;0.001). However, there was no correlation between pain and the β–NGF/sLNGFR ratio (r=-0.08, p&gt;0.05). TNF-α positively correlated with β–NGF (r= 0.83, p&lt;0.001), NT-3 (r= 0.66, p&lt;0.01), and BDNF (r= 0.50, p&lt;0.05) and negatively with ProNGF (r= -0.74, p&lt;0.01). Additionally, TNF-α positively correlated with TrkA (r=0.62, p&gt;0.05) and sLNGFR (r=0.26, p&gt;0.05). <h3>Conclusion</h3> Our results align well with the previously-proposed β–NGF pain molecular pathway and suggest that inflammation-related endogenous cleavage of sLNGFR, but not TrkA may modulate pain <i>in vivo</i> in OA as sLNGFR act as sink of the endogenous NGF. These novel findings may provide new avenues for safe and effective pain reduction strategies in OA. <h3>References</h3> [1](2017), 110–18 [2]Walsh, D. A., D. F. McWilliams, M. J. Turley, M. R. Dixon, R. E. Fransès, P. I. Mapp, and D. Wilson, <i>Rheumatology (Oxford),</i> 49. 10 (2010), 1852-61 [3]Weskamp, G., J. Schlöndorff, L. Lum, J. D. Becherer, T. W. Kim, P. Saftig, D. Hartmann, G. Murphy, and C. P. Blobel, ', <i>J Biol Chem,</i> 279. 6 (2004), 4241-9 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Ala Altaie: None declared, Mark Campbell: None declared, Rachel Doyle Employee of: work for Levicept Ltd, Discovery Park, Sandwich, United Kingdom, Heather Owston: None declared, Elena Jones: None declared, Robert Feibel: None declared, Simon Westbrook Shareholder of: Levicept Ltd, Discovery Park, Sandwich, United Kingdom, Dennis McGonagle: None declared.